The incidence of cancer has significantly decreased in the United States with improved long-term survival rates due to earlier diagnosis and better treatments. But for primary liver cancer – known as hepatocellular carcinoma (HCC) – progress has been limited and the prognosis remains grim.

According to the National Cancer Institute, primary liver cancer has become the fastest growing cancer in the U.S., and the numbers are expected to rise even more in the next 20 years, due to surging cases of chronic hepatitis B and C infections. Liver cancer is currently the fifth most common cancer in the world, and ranks eighth among leading causes of cancer death for Americans.

If only, many experts say, there was a good way to find the cancer early enough to effectively treat it. With this in mind, the Hepatitis B Foundation (HBF) convened its 12th annual Princeton Workshop on Oct. 24-25, 2006 in Princeton, NJ, to focus on identifying the most promising biomarkers for development to improve early detection.

This year, 30 thought leaders were invited to review and discuss biomarkers in the research pipeline, and make recommendations about which seemed the most promising to reach the clinic. The workshop was held in partnership with the National Cancer Institute’s Early Detection Research Network (EDRN), whose mission is to find biomarkers for a host of cancers.

Workshop participants unanimously agreed that alternative, non-invasive markers need to be developed for the early detection of liver cancer. Currently, a painful liver biopsy is the standard method for diagnosis.

“The ideal biomarker would be used in a blood test that could predict who has liver cancer or is at high risk,” said Robert Gish, M.D., medical director of the Liver Transplant Program at California Pacific Medical Center in San Francisco. “It could also be used to determine both an individual’s risk of recurrence or treatment response.”

According to Paul Wagner, Ph.D., program director of the National Cancer Institute’s Cancer Biomarkers Research Group, “A challenge is to find a marker that picks up most people with cancer but doesn’t give a lot of false positives.

”For decades, the most widely used biochemical blood test for liver cancer has been alpha-fetoprotein (AFP), which is a protein normally made by immature liver cells in the fetus. This test, however, is controversial because it is not highly sensitive or specific enough for liver cancer.

Most Promising Biomarkers

Of the eight biomarkers discussed at the workshop, several stood out as most promising. Elevated levels of the biomarker, AFP (L3), or fucosylated AFP, a slightly different version of AFP, is a sign of heightened risk of developing liver cancer, for example, said Gish. It was recently approved by the U.S. FDA as a “risk marker” for primary liver cancer.

DCP (des-gamma-carboxy prothrombin), an abnormal protein apparently made by cancer cells, is another promising biomarker. Workshop attendee Jorge Marrero, M.D., at the University of Michigan, is working with a company, Wako Diagnostics, in Richmond, VA, to develop a panel of biomarkers that includes DCP.

GP73 (a golgi protein marker) and its fucosylated form – discovered by Timothy Block , Ph.D. and Anand Mehta, D.Phil. (HBF and Drexel U.) – was found to correlate with a diagnosis of liver cancer, even if the standard AFP test is negative.

Continuing with a “glycosylation” theme, glypican and glyco-cirrhosis are biomarkers that show great promise. In addition, viral mutant and HBV-induced host gene markers that are in the research pipeline were also discussed.

Large-scale validation studies for a number of liver cancer biomarkers, including DCP and AFP (L3), are being organized by the National Cancer Institute’s EDRN. Studies will compare the use of these biomarkers in 450 patients with liver cancer, and 450 patients with cirrhosis as controls, to see which works best in identifying cancer. Biomarkers that are deemed more useful than the standard AFP would be tested in prospective screening trials.

Early detection of primary liver cancer, of which 80% is caused by chronic hepatitis B, is critical for its effective management. Current methods, however, are very limited in usefulness or practicality. With a five year survival rate of liver cancer less than 5%, the development of effective biomarkers is urgently needed to save lives.

Steve Benowitz, science writer
Philadelphia, PA